SEARCH · PubMed Health

Results for “repressive histone mark”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources

PubMed2001

MAP kinases mediate UVB-induced phosphorylation of histone H3 at serine 28.

Histone H3 phosphorylation is related closely to chromatin remodeling and chromosome condensation. H3 phosphorylation at serine 28 is coupled with mitotic chromosome condensation in diverse mammalian cell lines. However, the pathway that mediates phosphorylation of H3 at serine 28 is unknown. In the present study, ERK1, ERK2, or p38 kinase strongly phosphorylated H3 at serine 28 in vitro. JNK1 or JNK2 was able also to phosphorylate H3 at serine 28 in vitro but to a lesser degree. UVB irradiation markedly induced phosphorylation of H3 at serine 28 in JB6 Cl 41 cells. PD 98059, a MEK1 inhibitor, and SB 202190, a p38 kinase inhibitor, efficiently repressed UVB-induced H3 phosphorylation at serine 28. Expression of dominant negative mutant (DNM) ERK2 in JB6 Cl 41 cells totally blocked UVB-induced phosphorylation of H3 at serine 28. Additionally, DNM p38 kinase or DNM JNK1 partially blocked UVB-induced H3 phosphorylation at serine 28. Furthermore, UVB-induced H3 phosphorylation at serine 28 was inhibited in Jnk1(-/-) cells but not in Jnk2(-/-) cells. These results suggest that UVB-induced H3 phosphorylation at serine 28 may be mediated by mitogen-activated protein kinases.

Animals↗

PubMed2001

Involvement of histone deacetylase at two distinct steps in gene regulation during intestinal development in Xenopus laevis.

Amphibian metamorphosis is marked by dramatic thyroid hormone (T(3))-induced changes including de novo morphogenesis, tissue remodeling and organ resorption through programmed cell death. These changes involve cascades of gene regulation initiated by thyroid hormone and its receptors. Previous studies suggest that chromatin remodeling involving changes in core histone acetylation plays a fundamental role in transcriptional regulation. A basic model has been suggested where targeted histone deacetylation is involved in transcriptional repression and histone acetylation is involved in transcriptional activation. On the other hand, the developmental roles of histone acetylation remain to be elucidated. Here we demonstrate that tadpole treatment with trichostatin A, a specific potent histone deacetylase inhibitor, blocks metamorphosis. Gene expression analyses show that trichostatin A induces the release of T(3)-response gene repression without affecting T(3)-induction of direct T(3)-response genes. However, the drug blocks the regulation of late T(3)-response genes, which may be responsible for its inhibitory effects on metamorphosis. These data support a role of deacetylases in transcriptional repression by unliganded T(3) receptor during premetamorphosis and another role at a downstream step of the gene regulation cascade induced by T(3) during metamorphosis.

Animals↗

PubMed2006

Silencing by plant Polycomb-group genes requires dispersed trimethylation of histone H3 at lysine 27.

The plant Polycomb-group (Pc-G) protein CURLY LEAF (CLF) is required to repress targets such as AGAMOUS (AG) and SHOOTMERISTEMLESS (STM). Using chromatin immunoprecipitation, we identify AG and STM as direct targets for CLF and show that they carry a characteristic epigenetic signature of dispersed histone H3 lysine 27 trimethylation (H3K27me3) and localised H3K27me2 methylation. H3K27 methylation is present throughout leaf development and consistent with this, CLF is required persistently to silence AG. However, CLF is not itself an epigenetic mark as it is lost during mitosis. We suggest a model in which Pc-G proteins are recruited to localised regions of targets and then mediate dispersed H3K27me3. Analysis of transgenes carrying AG regulatory sequences confirms that H3K27me3 can spread to novel sequences in a CLF-dependent manner and further shows that H3K27me3 methylation is not sufficient for silencing of targets. We suggest that the spread of H3K27me3 contributes to the mitotic heritability of Pc-G silencing, and that the loss of silencing caused by transposon insertions at plant Pc-G targets reflects impaired spreading.

AGAMOUS Protein, Arabidopsis↗

PubMed2005

The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.

Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbalpha has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbalpha mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbalpha dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbalpha directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbalpha.

ARNTL Transcription Factors↗

PubMed2005

Expression patterns and post-translational modifications associated with mammalian histone H3 variants.

Covalent histone modifications and the incorporation of histone variants bring about changes in chromatin structure that in turn alter gene expression. Interest in non-allelic histone variants has been renewed, in part because of recent work on H3 (and other) histone variants. However, only in mammals do three non-centromeric H3 variants (H3.1, H3.2, and H3.3) exist. Here, we show that mammalian cell lines can be separated into two different groups based on their expression of H3.1, H3.2, and H3.3 at both mRNA and protein levels. Additionally, the ratio of these variants changes slightly during neuronal differentiation of murine ES cells. This difference in H3 variant expression between cell lines could not be explained by changes in growth rate, cell cycle stages, or chromosomal ploidy, but rather suggests other possibilities, such as changes in H3 variant incorporation during differentiation and tissue- or species-specific H3 variant expression. Moreover, quantitative mass spectrometry analysis of human H3.1, H3.2, and H3.3 showed modification differences between these three H3 variants, suggesting that they may have different biological functions. Specifically, H3.3 contains marks associated with transcriptionally active chromatin, whereas H3.2, in contrast, contains mostly silencing modifications that have been associated with facultative heterochromatin. Interestingly, H3.1 is enriched in both active and repressive marks, although the latter marks are different from those observed in H3.2. Although the biological significance as to why mammalian cells differentially employ three highly similar H3 variants remains unclear, our results underscore potential functional differences between them and reinforce the general view that H3.1 and H3.2 in mammalian cells should not be treated as equivalent proteins.

Animals↗

PubMed2001

Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations, invariably involving the retinoic acid receptor alpha (RAR alpha) gene fused to one of several distinct loci, including the PML or PLZF genes, involved in t(15;17) or t(11;17), respectively. Patients with t(15;17) APL respond well to retinoic acid (RA) and other treatments, whereas those with t(11;17) APL do not. The PML-RAR alpha and PLZF-RAR alpha fusion oncoproteins function as aberrant transcriptional repressors, in part by recruiting nuclear receptor-transcriptional corepressors and histone deacetylases (HDACs). Transgenic mice harboring the RAR alpha fusion genes develop forms of leukemia that faithfully recapitulate both the clinical features and the response to RA observed in humans with the corresponding translocations. Here, we investigated the effects of HDAC inhibitors (HDACIs) in vitro and in these animal models. In cells from PLZF-RAR alpha/RAR alpha-PLZF transgenic mice and cells harboring t(15;17), HDACIs induced apoptosis and dramatic growth inhibition, effects that could be potentiated by RA. HDACIs also increased RA-induced differentiation. HDACIs, but not RA, induced accumulation of acetylated histones. Using microarray analysis, we identified genes induced by RA, HDACIs, or both together. In combination with RA, all HDACIs tested overcame the transcriptional repression exerted by the RAR alpha fusion oncoproteins. In vivo, HDACIs induced accumulation of acetylated histones in target organs. Strikingly, this combination of agents induced leukemia remission and prolonged survival, without apparent toxic side effects.

Animals↗

PubMed2006

Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications.

Covalent histone post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitylation play pivotal roles in regulating many cellular processes, including transcription, response to DNA damage, and epigenetic control. Although positive-acting post-translational modifications have been studied in Saccharomyces cerevisiae, histone modifications that are associated with transcriptional repression have not been shown to occur in this yeast. Here, we provide evidence that histone sumoylation negatively regulates transcription in S. cerevisiae. We show that all four core histones are sumoylated and identify specific sites of sumoylation in histones H2A, H2B, and H4. We demonstrate that histone sumoylation sites are involved directly in transcriptional repression. Further, while histone sumoylation occurs at all loci tested throughout the genome, slightly higher levels occur proximal to telomeres. We observe a dynamic interplay between histone sumoylation and either acetylation or ubiquitylation, where sumoylation serves as a potential block to these activating modifications. These results indicate that sumoylation is the first negative histone modification to be identified in S. cerevisiae and further suggest that sumoylation may serve as a general dynamic mark to oppose transcription.

Acetylation↗

PubMed2007

Linker histone HIS-24 (H1.1) cytoplasmic retention promotes germ line development and influences histone H3 methylation in Caenorhabditis elegans.

RNA interference with one of the eight Caenorhabditis elegans linker histone genes triggers desilencing of a repetitive transgene and developmental defects in the hermaphrodite germ line. These characteristics are similar to the phenotype of the C. elegans Polycomb group genes mes-2, mes-3, mes-4, and mes-6 (M. A. Jedrusik and E. Schulze, Development 128:1069-1080, 2001; I. Korf, Y. Fan, and S. Strome, Development 125:2469-2478, 1998). These Polycomb group proteins contribute to germ line-specific chromatin modifications. Using a his-24 deletion mutant and an isoform-specific antibody, we characterized the role of his-24 in C. elegans germ line development. We describe an unexpected cytoplasmic retention of HIS-24 in peculiar granular structures. This phenomenon is confined to the developing germ lines of both sexes. It is strictly dependent on the activities of the chromatin-modifying genes mes-2, mes-3, mes-4, and mes-6, as well as on the C. elegans sirtuin gene sir-2.1. A temperature shift experiment with a mes-3(ts) mutant revealed that mes gene activity is required in a time window ranging from L3 to the early L4 stage before the onset of meiosis. We find that the his-24(ok1024) mutant germ line is characterized by an increased level of the activating H3K4 methylation mark concomitant with a decrease of the repressive H3K9 methylation. In the germ line of his-24(ok1024) mes-3(bn35) double mutant animals, the repressive H3K27 methylation is more reduced than in the respective mes single mutant. These observations distinguish his-24 as an unusual element in the developmental regulation of germ line chromatin structure in C. elegans.

Active Transport, Cell Nucleus↗

PubMed2005

Caveolin and GLT-1 gene expression is reciprocally regulated in primary astrocytes: association of GLT-1 with non-caveolar lipid rafts.

Caveolae represent membrane microdomains acting as integrators of cellular signaling and functional processes. Caveolins are involved in the biogenesis of caveolae and regulate the activity of caveolae-associated proteins. Although caveolin proteins are found in the CNS, the regulation of caveolins in neural cells is poorly described. In the present study, we investigated different modes and mechanisms of caveolin gene regulation in primary rat astrocytes. We demonstrated that activation of cAMP-dependent signaling pathways led to a marked reduction in protein levels of caveolin-1/-2 in cortical astrocytes. Application of transforming growth factor-alpha (TGF-alpha) also resulted in a decrease of caveolin-1/-2 expression. Decreased caveolin protein levels were mirrored by diminished caveolin gene transcription. The repressive effect of TGF-alpha on caveolin-1 expression was MAP kinase-independent and partly mediated through the PI3-kinase pathway. Further downstream, inhibition of histone deacetylases abrogated TGF-alpha effects, suggesting that chromatin remodeling processes could contribute to caveolin-1 repression. Intriguingly, alterations of caveolin gene expression in response to cAMP or TGF-alpha coincided with reciprocal and brain-region specific changes in glial glutamate transporter GLT-1 expression. The reciprocal regulation of caveolin-1 and GLT-1 expression might be gated through a common PI3-kinase dependent pathway triggered by TGF-alpha. Finally, we showed that GLT-1 is located in non-caveolar lipid rafts of cortical astrocytes. In conclusion, this study highlights the occurrence of the reciprocal regulation of caveolin and GLT-1 expression during processes such as astrocyte differentiation via common signaling pathways. We also provide strong evidence that GLT-1 itself is concentrated in lipid rafts, inferring an important role for glial glutamate transporter function.

Animals↗

PubMed2006

The X and Y chromosomes assemble into H2A.Z-containing [corrected] facultative heterochromatin [corrected] following meiosis.

Spermatogenesis is a complex sequential process that converts mitotically dividing spermatogonia stem cells into differentiated haploid spermatozoa. Not surprisingly, this process involves dramatic nuclear and chromatin restructuring events, but the nature of these changes are poorly understood. Here, we linked the appearance and nuclear localization of the essential histone variant H2A.Z with key steps during mouse spermatogenesis. H2A.Z cannot be detected during the early stages of spermatogenesis, when the bulk of X-linked genes are transcribed, but its expression begins to increase at pachytene, when meiotic sex chromosome inactivation (MSCI) occurs, peaking at the round spermatid stage. Strikingly, when H2A.Z is present, there is a dynamic nuclear relocalization of heterochromatic marks (HP1beta and H3 di- and tri-methyl K9), which become concentrated at chromocenters and the inactive XY body, implying that H2A.Z may substitute for the function of these marks in euchromatin. We also show that the X and the Y chromosome are assembled into facultative heterochromatic structures postmeiotically that are enriched with H2A.Z, thereby replacing macroH2A. This indicates that XY silencing continues following MSCI. These results provide new insights into the large-scale changes in the composition and organization of chromatin associated with spermatogenesis and argue that H2A.Z has a unique role in maintaining sex chromosomes in a repressed state.

Animals↗

PubMed1967

Histones of genetically active and inactive chromatin.

It has frequently been proposed that a variation in the relative content of lysine-rich, moderately lysine-rich, and arginine-rich histones might provide a mechanism by which specific portions of the genome may be genetically regulated. This possibility was investigated by comparing the electrophoretic pattern of these three fractions in cells differing markedly in their content of genetically active and genetically inactive chromatin. Three models were used: heterochromatin versus euchromatin; metaphase cells versus interphase cells, and mature lymphocytes versus phytohemagglutinin-stimulated lymphocytes. In no case was there a significant difference in the histone patterns of these contrasting models. It is concluded that, although histones may act as a generalized repressor and structural component of chromatin, factors other than a variation in histone pattern may be responsible for repression or derepression of specific segments of the genome.

Animals↗

PubMed1994

A role for histones H2A/H2B in chromatin folding and transcriptional repression.

Histone octamers or histone H3/H4 tetramers were reconstituted onto either closed circular plasmids containing a single Xenopus 5S rRNA gene or a reiterated array of Lytechinus 5S rRNA genes. All "reconstitutes" were found to undergo both Na(+)-dependent and Mg(2+)-dependent compaction. However, in each case, the compaction of nucleosomal templates containing H2A/H2B was much more extensive than compaction of templates containing only H3/H4 tetramers. Inclusion of 5 mM MgCl2 in the transcription buffer increased the level of compaction of nucleosomal templates and led to a marked inhibition of both transcription initiation and elongation by RNA polymerase III. The inhibitory effect of Mg2+ was reduced significantly when DNA templates contained only H3/H4 tetramers, consistent with their lesser extent of Mg(2+)-dependent compaction. Thus, the removal of histones H2A/H2B from nucleosomal arrays enhances gene activity, in part because of decreased levels of chromatin folding.

Animals↗

PubMed2003

EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells.

The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive prostate cancer. Here we investigate the functional role of EZH2 in cancer cell invasion and breast cancer progression. EZH2 transcript and protein were consistently elevated in invasive breast carcinoma compared with normal breast epithelia. Tissue microarray analysis, which included 917 samples from 280 patients, demonstrated that EZH2 protein levels were strongly associated with breast cancer aggressiveness. Overexpression of EZH2 in immortalized human mammary epithelial cell lines promotes anchorage-independent growth and cell invasion. EZH2-mediated cell invasion required an intact SET domain and histone deacetylase activity. This study provides compelling evidence for a functional link between dysregulated cellular memory, transcriptional repression, and neoplastic transformation.

Breast↗

PubMed2001

Transcriptional repression of the anti-apoptotic survivin gene by wild type p53.

Survivin is a member of the inhibitor of apoptosis family. This apoptosis inhibitor also has an evolutionarily conserved role as a mitotic spindle checkpoint protein. Previous studies on p53-repressed genes have implicated several genes involved in the G(2)/M transition of the cell cycle as targets of negative regulation by p53. However, few targets of p53 repression that are anti-apoptotic have been identified. This study identifies the anti-apoptotic survivin gene as a p53-repressed gene. Notably, Survivin repression by p53 is shown to be distinct from p53-dependent growth arrest. Chromatin immunoprecipitations indicate that p53 binds the survivin promoter in vivo; immunobinding studies indicate that this site overlaps with a binding site for E2F transcription factors and is subtly distinct from a canonical p53-transactivating element. The survivin-binding site contains a 3-nucleotide spacer between the two decamer "half-sites" of the p53 consensus element; deletion of this spacer is sufficient to convert the survivin site into a transactivating element. Finally, we show that overexpression of Survivin in cells sensitive to p53-dependent cell death markedly inhibits apoptosis induced by ultraviolet light. The identification of survivin as a p53 repressed gene should aid in the elucidation of the contribution of transcriptional repression to p53-dependent apoptosis.

Adenocarcinoma↗

PubMed2026

MacroH2A2-Enriched Domains Are Largely Stable Across the Cell Cycle but Focally Displaced at Mitotic Regulatory Elements.

The macroH2A variants mH2A1 and mH2A2 are structurally similar but not identical. Our previous study demonstrated that mH2A1 is reloaded during cell-cycle progression, but whether mH2A2 follows similar dynamics has remained unclear. Here, we used native ChIP-seq in synchronized Huh-7 cells to profile both variants at G1/S and G2/M. Although mH2A1- and mH2A2-enriched domains overlapped extensively, mH2A2 domains were largely stable across the cell cycle, in sharp contrast to the dynamic reloading of mH2A1. Only a small subset of mH2A2 domains showed phase-specific deposition or displacement. Among these, G1/S-unique mH2A2 domains were preferentially located in the active A compartment and coincided with reduced chromatin accessibility at binding sites for cell-cycle regulators. These G1/S-unique domains co-localize with genes involved in mitotic progression within the same A compartment, suggesting potential regulatory roles in both chromatin organization and transcriptional regulation. These findings refine the classical view of macroH2A variants as static repressive marks: mH2A2 is not entirely static, but its cell-cycle dynamics are far more restricted than those of its paralog mH2A1, occurring only at a small subset of genomic loci, with a regulatory logic distinct from that of mH2A1.

Histones↗

PubMed2005

COUP-TF interacting protein 2 represses the initial phase of HIV-1 gene transcription in human microglial cells.

Human immunodeficiency virus type 1 (HIV-1) gene transcription is characterized by two temporally distinct phases. While the initial phase relies solely on cellular transcription factors, the subsequent phase is activated by the viral Tat transactivator. We have previously reported that the subsequent phase of viral gene transcription can be repressed by the chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2) in human microglial cells [O. Rohr, D. Lecestre, S. Chasserot-Golaz, C. Marban, D. Avram, D. Aunis, M. Leid and E. Schaeffer (2003), J. Virol., 77, 5415-5427]. Here, we demonstrate that CTIP proteins also repress the initial phase of HIV-1 gene transcription, mainly supported by the cellular transcription factors Sp1 and COUP-TF in microglial cells. We report that CTIP2 represses Sp1- and COUP-TF-mediated activation of HIV-1 gene transcription and viral replication as a result of physical interactions with COUP-TF and Sp1 in microglial nuclei. Using laser confocal microscopy CTIP2 was found to colocalize with Sp1, COUP-TF and the heterochromatin-associated protein Hp1alpha, which is mainly detected in transcriptionally repressed heterochromatic region. Moreover, we describe that CTIP2 can be recruited to the HIV-1 promoter via its association with Sp1 bound to the GC-box sequences of the long terminal repeat (LTR). Since our findings demonstrate that CTIP2 interacts with the HIV-1 proximal promoter, it is likely that CTIP2 promotes HIV-1 gene silencing by forcing transcriptionally repressed heterochromatic environment to the viral LTR region.

COUP Transcription Factors↗

PubMed2003

Balance between acetylation and methylation of histone H3 lysine 9 on the E2F-responsive dihydrofolate reductase promoter.

Epigenetic marks that specify silent heterochromatic domains in eucaryotic genomes include methylation of histone H3 lysine 9. Strikingly, active loci in the vicinity of silent domains are sometimes characterized by acetylation of histone H3 lysine 9, suggesting that the balance between these two competitive modifications is important for the establishment of specific chromatin structures. Some euchromatic genes, targeted by the retinoblastoma protein Rb, are also believed to be regulated by histone H3 lysine 9 methylation. Here, we study the dihydrofolate reductase promoter, which is repressed in G0 and at the beginning of G1 by p107 or p130, two Rb-related proteins. We found that these two pocket proteins share with Rb the ability to associate with the histone methyl transferase SUV39H1. SUV39H1 can be recruited to the E2F transcription factor and functions as a transcriptional corepressor. With ChIP assays followed by real-time PCR, we showed that K9 of histone H3 evolves from a hypermethylated state in G0 to a hyperacetylated state at the G1/S transition. Taken together, these results indicate that the temporal regulation of euchromatic promoters may involve controlling the balance between methylation and acetylation of histone H3 lysine 9, a feature previously described for the spatial regulation of chromatin function.

3T3 Cells↗

PubMed2004

Divergent roles of a pair of homologous jumonji/zinc-finger-class transcription factor proteins in the regulation of Arabidopsis flowering time.

Flowering in Arabidopsis thaliana is controlled by multiple pathways, including the photoperiod pathway and the FLOWERING LOCUS C (FLC)-dependent pathway. Here, we report that a pair of related jumonji-class transcription factors, EARLY FLOWERING 6 (ELF6) and RELATIVE OF EARLY FLOWERING 6 (REF6), play divergent roles in the regulation of Arabidopsis flowering. ELF6 acts as a repressor in the photoperiod pathway, whereas REF6, which has the highest similarity to ELF6, is an FLC repressor. Ectopic expression studies and expression pattern analyses show that ELF6 and REF6 have different cellular roles and are also regulated differentially despite their sequence similarities. Repression of FLC expression by REF6 accompanies histone modifications in FLC chromatin, indicating that the transcriptional regulatory activity of this class of proteins includes chromatin remodeling. This report demonstrates the in vivo functions of this class of proteins in higher eukaryotes.

Amino Acid Sequence↗